The general aim of the proposal is to study the pathogenesis and pathophysiology of hypercholesterolemia or atherosclerosis-induced impotence. The effects of hypercholesterolemia or atherosclerosis on the reactivity of corporal smooth muscle, corporal endothelium, penile cavernosal arteries and cellular mechanism of muscle relaxation will be investigated. Majority of cases of impotence due to corporal veno-occlusive dysfunction are associated with vascular risk factors such as smoking, hypercholesterolemia, atherosclerosis and hypertension. The pathogenesis and pathophysiology of atherosclerotic impotence have not been investigated. The proposed study will lead to improved understanding of the effects of hypercholesterolemia or atherosclerosis on the physiology of erectile tissue and has the potential to provide great information on the fundamental mechanisms of erectile dysfunction. Identification of the physiologic alterations in erectile tissue due to hypercholesterolemia or atherosclerosis may lead to improved diagnosis and more effective treatment of organic erectile dysfunction. The animal model of atherosclerotic impotence is developed by balloon deendothelialization of the iliac arteries and providing a cholesterol-rich diet (0.5% cholesterol and 4% peanut oil). In the proposed study, the New Zealand white rabbits will be randomly divided into four groups: 1) ballooned cholesterol diet, 2) ballooned regular diet, 3) cholesterol diet alone and 4) regular diet alone. At week 10, 20, 30 or 40, in all animals, erectile response to electrical stimulation of the pelvic nerve or intracavernosal injection of papaverine and phentolamine will be examined. The function of corporal veno-occlusion will be evaluated with dynamic infusion cavernosometry and cavernosography. Impotent animals including those with corporal veno-occlusive dysfunction will be identified. After this the animals will be sacrificed with intravenous injection of pentobarbital and the corporal tissue will be isolated for further studies. To study the effects of hypercholesterolemia or atherosclerosis on corporal smooth muscle tone, reactivity of corporal smooth muscle and endothelium, release of nitric oxide and accumulation of cyclic guanosine monophosphate (cGMP) in the corporal tissue will be compared between the four groups. The reactivity of corporal smooth muscle and corporal endothelium will be studied in the organ bath. The release of nitric oxide and accumulation of cGMP in the corporal tissue during muscle relaxation will be determined with radioimmunoassay. To study the effects of hypercholesterolemia or atherosclerosis on the physiology of penile microvasculature, alterations in the reactivity of cavernosal arteries will be examined in the wire myograph. All results will be compared between the four groups in an attempt to establish a relationship between the in vivo and in vitro parameters of erectile dysfunction.